Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast Journal Article
| Authors: | Natrajan, R.; Wilkerson, P. M.; Marchiò, C.; Piscuoglio, S.; Ng, C. K. Y.; Wai, P.; Lambros, M. B.; Samartzis, E. P.; Dedes, K. J.; Frankum, J.; Bajrami, I.; Kopec, A.; Mackay, A.; A'Hern, R.; Fenwick, K.; Kozarewa, I.; Hakas, J.; Mitsopoulos, C.; Hardisson, D.; Lord, C. J.; Kumar-Sinha, C.; Ashworth, A.; Weigelt, B.; Sapino, A.; Chinnaiyan, A. M.; Maher, C. A.; Reis-Filho, J. S. |
| Article Title: | Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast |
| Abstract: | Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities. |
| Keywords: | immunohistochemistry; mitogen activated protein kinase; functional assessment; unclassified drug; gene mutation; somatic mutation; mutation; case-control studies; molecular genetics; cell proliferation; phenotype; genetic predisposition to disease; breast cancer; gene expression; carcinoma, papillary; tumor markers, biological; cell line, tumor; mutational analysis; breast neoplasms; time factors; gene expression regulation, neoplastic; oligonucleotide array sequence analysis; gene disruption; cancer cell; breast carcinoma; gene fusion; fusion gene; neoplasm invasiveness; dna mutational analysis; gene dosage; sequence analysis, rna; comparative genomic hybridization; dna extraction; rna extraction; rna sequence; glucose transporter 1; micropapillary carcinoma; microdissection; dna copy number variations; micropapillary; copy number variation; peptides and proteins; humans; female; priority journal; article; cdk12; fusion transcripts; somatic mutation profiling; parp inhibitors; rna sequencing; aurka protein; bcas4 protein; faf1 protein |
| Journal Title: | Journal of Pathology |
| Volume: | 232 |
| Issue: | 5 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2014-04-01 |
| Start Page: | 553 |
| End Page: | 565 |
| Language: | English |
| DOI: | 10.1002/path.4325 |
| PUBMED: | 24395524 |
| PROVIDER: | scopus |
| PMCID: | PMC4013428 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 -- Export Date: 1 August 2014 -- CODEN: JPTLA -- Source: Scopus |
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